Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.
Nitric oxide (NO)-generating agents induce vasodilatation, and are beneficial in a variety of cardiovascular disorders including angina pectoris, hypertensive emergencies, and congestive heart failure (Elliott W. J. (2004) J. Clin. Hypertension 6:S87-S92; Vaughan C. J., and Delanty N. (2000) Lancet 356:411-417; Teerlink J. R. (2005) Am. J. Cardiol. 96:59 G-67G; Stough W. G. et al. (2005) Amer. J. Cardiology 96:41 G-46G). NO has multiple physiological effects, most notably relaxing vascular smooth muscle cells in both the venous and arterial systems; thus, it is used clinically as both a pre- and after-load reducing agent, and an anti-hypertensive drug (Lloyd-Jones D M et al. (1996) Annu. Rev. Med. 47:365-75). Its major drawback for clinical use is that it is an unstable gas, and, although inhaled NO is used for pulmonary hypertension, administering it presents technical challenges (Haj R M et al. (2006) Curr. Opin. Anaesthesiol. 19:88-95). NO is, therefore, commonly provided as an organic nitrate, such as nitroglycerin (glyceryl trinitrate), isosorbide dintrate, or pentaerythritol tetranitrate. These compounds are thus not pure NO releasing agents, and, at least in the case of nitroglycerin, drug tolerance develops as a consequence of its biotransformation to NO (Sydow K et al. (2004) J. Clin. Invest. 113:482-9; Daiber A et al. (2005) Am. J. Cardiol. 96:25i-36i; and, Parker J D (2004) J. Clin. Invest. 113:352-4). The only direct NO releasing drug clinically available in the United States is sodium nitroprusside, but five cyanide ions are released for every NO molecule, limiting its use because of cyanide toxicity (Schulz V (1984) Clin. Pharmacokinet. 9:239-51; Posner M A et al. (1976) Anesthesiology 44:330-5; Merrifiedl A J B (1974) Br. J. Anaesthesia 46:324). Clearly, better NO-generating drugs are needed (Thatcher G R (2005) Curr. Top. Med. Chem. 5:597-601).
The reactions of NO with cobalamin (vitamin B,2) and cobinamide were recently studied; the latter is a cobalamin precursor lacking a benzimidazole group (Sharma V S et al. (2003) Biochemistry 42:8900-8). The cobalt atom in cobalamin and cobinamide can exist in either a +3 or +2 valency state. Under ambient, oxygen-exposed conditions, the +3 valency state predominates, and cobinamide+3 is refereed to as “cobinamide;” cobinamide+2 is referred to as “Cbi(II).” At neutral pH, NO does not bind to cobinamide, but reduces it to Cbi(II), in the process being oxidized to nitrite; NO then binds with relatively high affinity to Cbi(II) (KA-1010 M′1), yielding nitrosyl-cobinamide (NO-Cbi) (Sharma V S et al. (2003) Biochemistry 42:8900-8). The reaction of NO with Cbi(II) is fully reversible.